tbuckley/cabot-search huggingface dataset:
Abstract 3289: PD-1 peptide/IL-12 combination gene therapy for the treatment of melanoma
Authors: Loree Heller, Guilan Shi, Jody Synowiec, Richard Heller
Journal: Cancer Research (2022)

Abstract Immune checkpoint inhibitors (ICIs) such as PD-1 targeting antibodies nivolumab and pembrolizumab are FDA approved as therapies for many cancers. These ICIs inhibit PD-1 ligand binding, removing interference with T cell function, allowing T cell proliferation, and restoring the anti-tumor activity. Potential factors predicting checkpoint blockade success include PD-L1 expression, the presence of tumor infiltrating lymphocytes, microsatellite instability, and tumor mutational burden. ICIs are most effective clinically in combination therapies. Here, we devised a simple ICI gene therapy as a possible alternative to traditional and expensive monoclonal antibodies. We designed plasmids encoding the mouse sequences homologous to the nivolumab and pembrolizumab binding regions, which overlap the PD-1 ligand binding site. We hypothesized that, when produced intratumorally, each PD-1 peptide should bind PD-L1 and block T cell binding. Since B16F10 mouse melanoma cells and tumors express PD-L1, we tested this theory in this model. We directly demonstrated peptide-PD-L1 binding histologically on B16F10 mouse melanoma tumors. Systemic expression of the encoded peptides did not induce changes in general demeanor, discomfort or weight changes in mice, implying that intratumor expression would also be non-toxic. We then tested these peptide plasmids therapeutically. Intratumor electroporation delivery of the peptide plasmids to palpable B16F10 mouse melanoma tumors significantly increased tumor doubling time and induced approximately 10% long-term tumor regression. Delivery of a plasmid encoding IL-12 induced long-term tumor regression in approximately 40% of mice as well as a reduction myeloid-derived suppressor cells and T regulatory cells and an increase infiltration of CD8+ T cells, creating an inflamed tumor microenvironment. This modulation of the tumor microenvironment suggested the potentiation of a combination therapy. This combination synergistically increased long-term regression to 80-100%, depending on the peptide plasmid delivered, over either PD-1 peptide or IL-12 gene therapy alone. These results demonstrated that the delivery of immune regulators with differing activities may be a promising and potentially inexpensive alternative to monoclonal antibody therapies. Citation Format: Loree Heller, Guilan Shi, Jody Synowiec, Richard Heller. PD-1 peptide/IL-12 combination gene therapy for the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3289.
Abstract 282: Breast cancer microphysiological systems based on human breast tissue
Authors: Frank H. Lau, C. Ethan Byrne, Loren Brown, Jake Fontenot, Rafael P. Tiongco, Rakesh R. Gurrala, Jonathan Cuccia, Andrew DiNardo, Matthew Burow, Elizabeth C. Martin
Journal: Cancer Research (2022)

Abstract Breast cancer is a heterogeneous disease that accumulates signaling cues from cell intrinsic and extrinsic factors. Many of these cues are derived from the tumor microenvironment (TME). The TME modulates cellular proliferation, survival, and resistance to therapy in breast cancer. The TME is a bio-mechanical and biochemical reservoir for extracellular matrix and signaling factors (cytokines, growth factors, lipids, and hormones). In addition, the TME houses a diverse array of cell populations including adipocytes, vasculature, stem cells, immune cells, and cancer cells. Currently models do not reprpoduce the TME in vitro. The goal of this study was to develop a complex and dynamic micro-physiological 3D tumor model for pre-clinical studies using the native human breast environment. We developed a technique to maintain healthy human breast tissue (HBT) alive ex vivo for up to 8 weeks in the presence of breast cancer (BC) cells creating a breast cancer micro-physiological system (BC-MPS). In this study, we demonstrate alterations to lipid accumulation, matrix fiber remodeling, and cytokine profile in our BC-MPS system. We used RNA sequencing to detect breast cancer cell line signatures retained in the BC-MPS system. Results demonstrate retention of the breast cancer cell line transcriptome for a minimum of 14 days in vitro. In addition we identify alterations to genes associated with the TME, specifically the extracellular matrix and metabolism. Our novel model will allow for 1) real-time examination of BC-HBT interactions and 2) the isolation of BC-specific factors vs. patient-specific factors on the development and progression of BC. Citation Format: Frank H. Lau, C. Ethan Byrne, Loren Brown, Jake Fontenot, Rafael P. Tiongco, Rakesh R. Gurrala, Jonathan Cuccia, Andrew DiNardo, Matthew Burow, Elizabeth C. Martin. Breast cancer microphysiological systems based on human breast tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 282.
Case 18-2022: A 29-Year-Old Woman with Recurrent Fractures
Authors: Michael J. Econs, Daryl J. Selen, Rene Balza, Omar Zurkiya, Henry M. Kronenberg, Yin P. Hung
Journal: New England Journal of Medicine (2022)

A 29-year-old woman presented with recurrent bone fractures and hypophosphatemia. The patient had been well until 19 months before admission, when pain in the right foot developed. During the next 19 months, multiple fractures of the metatarsal bones of the right foot occurred. On admission, the blood phosphorus level was 1.0 mg per deciliter. A diagnostic test was performed.
Abstract 3114: PDX tumor growth comparisons in the ultra-immunodeficient NOD.CB17-<i>PrkdcscidIL2rgtm1</i>/Bcgen (B-NDG) mouse model
Authors: Michele Melton, Hongmei Jiang, Emma M. Hyddmark, Travis Rothrock
Journal: Cancer Research (2022)

Abstract The purpose of the study was to compare the growth of various PDX models in the two ultraimmunodeficient mouse models NSG™ (Jackson Laboratory) and B-NDG (Inotiv). Four breast cancer PDX models from the Washington University Human in Mouse (WHIM) collection, ER+ WHIM20 and WHIM81, Her2+ WHIM43, and triple negative WHIM5, and one melanoma PDX models generated by the Wistar institute, WM4071-2, was utilized. For models WHIM20, WHIM5, and WM4071-2 all mice were injected with tumor cells on the same day, whereas for WHIM43 BND-G mice were injected in two separate batches. The WHIM81 studies were carried out at different times for the NSG™ and B-NDG animal cohorts. Studies utilizing WHIM5, WHIM20, WHIM43 and WM4071-2, included a group of athymic nude mice as well. For all models, mice were injected with 1.5x106 cells/mouse. The cells were mixed 1:1 with PBS:Corning Matrigel GFR and the injection volume was 100 µL/mouse. Mice were housed in Innovive individually vented cages and consumed Teklad Global Rodent Diet 2019 throughout the study. Tumors were measured multiple times per week using Biopticon’s TumorImager™. For all models except WHIM81, the tumors grew well and with very similar rate in both B-NDG and NSG™ mice. WHIM20 and WHIM43 grew significantly slower in the Athymic nude mice compared to both of the ultraimmunodeficient mouse models, however, the growth of WHIM5 was comparable between all three models. The results from the WHIM81 model suggests faster growth in the B-NDG model compared to the NSG™, however, it is also possible that this is due to the different batches of tumor cells utilized at each implantation event. Thus, the B-NDG model represents a novel ultraimmunodeficient mouse model that can have great utility for tumor studies, particularly for hard to grow or slower growing tumor models. Citation Format: Michele Melton, Hongmei Jiang, Emma M. Hyddmark, Travis Rothrock. PDX tumor growth comparisons in the ultra-immunodeficient NOD.CB17-PrkdcscidIL2rgtm1/Bcgen (B-NDG) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3114.
Abstract 6380: Essential chemokine score as a potential surrogate for immune checkpoint therapy in pan cancer
Authors: Xuhui Bao, Liyi Xie
Journal: Cancer Research (2022)

Abstract The inhibition of the immune checkpoint axis of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has achieved significant anti-tumor therapeutic success, though it is still inadequate to ameliorate the dismal outcomes of the majority of cancer patients. Therefore, it is urgent and of interest in scrutinizing predictive indicators to enable a precision anti-tumor strategy, predict the therapeutic response, and better comprehend the mechanisms of resistance to immunotherapies. To evaluate the vigorous potential of CXCL9/10/11 score as a single, universal, and reliable surrogate to predict the response to anti-PD-1 therapy in different cancer types. The analyses in this study used the cancer genomic data from 31 different solid cancers in the Cancer Genome Atlas (TCGA) to calculate the CXCL9/10/11 score, CD274 expression, tumor mutational burden (TMB), and tumor immune phenotypes (IPs). The difference of CD274 expression, TMB, and tumor IPs was then compared between CXCL9/10/11 scoreLow and scoreHigh groups for each cancer type. Furthermore, this score was examined in two cohorts of patients with different cancer types treated with anti-PD-1 therapy to predict the expression of CD274, regression/progression status, and progression-free survival (PFS) between the scoreLow and scoreHigh groups. CD274 expression, TMB, and most tumor IPs were significantly elevated in CXCL9/10/11 scoreHigh group than in the scoreLow group among 12 different TCGA cancer types including breast cancer, lung cancer, colon cancer, melanoma, bladder cancer, and endometrial cancers. In two validation cohorts of 49 patients with lung cancer, melanoma, and head and neck cancer, and 85 patients with metastatic melanoma treated by anti-PD-1 therapy, respectively, scoreHigh tumors exhibited significantly high expression of CD274 than scoreLow tumors (p = 0.0006 and p = 0.0023, respectively). Significantly more patients in the scoreHigh group achieved post-treatment cancer regression than those patients in the scoreLow group (p = 0.0200 and p = 0.0427, respectively). The patients in the scoreHigh group enjoyed a significantly longer PFS than those in the scoreLow group (p = 0.0179 and p = 0.0229, respectively). Our findings suggest that CXCL9/10/11 score can serve as a single, universal, and reliable surrogate corresponding to CD274 expression, TMB, and tumor IPs within one variable among many different cancer types, and exhibits a vigorous and attractive potential to predict the therapeutic response to anti-PD-1 therapy in patients. Citation Format: Xuhui Bao, Liyi Xie. Essential chemokine score as a potential surrogate for immune checkpoint therapy in pan cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6380.
Abstract 502: The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis
Authors: Lisa Scarton, Ara Jo, Zhigang Xie, LaToya J. O’Neal, Juan M. Pena, Thomas J. George, Jiang Bian
Journal: Cancer Research (2022)

Abstract Cancer and type 2 diabetes (T2DM) are common diseases that have serious health consequences. T2DM is known to increase the risk for the development of many of the most common cancers. Metformin, one of the most commonly used drugs to treat T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on OS in patients with advanced cancer. We examined the relationship between metformin dose and OS in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers. Methods: We used a retrospective study design with cox proportional hazards regression analysis of the 2007-2016 of the Surveillance Epidemiology and End Results-Medicare dataset. Results: A total of 7,725 patients with T2DM and a least one targeted cancer was included in the analysis. Of those patients, 38.5% had been prescribed metformin. Patients who used metformin had significantly better OS in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69-0.76; p &amp;lt; 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; p &amp;lt; 0.001). The OS between patients who took metformin with average daily dose ≥ 1000mg or &amp;lt; 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93-1.08; p=0.90). Conclusions: Metformin use, regardless of dose, increases OS in older adults with advanced cancer. Additionally, OS was not significantly different across race or ethnicity. Citation Format: Lisa Scarton, Ara Jo, Zhigang Xie, LaToya J. O’Neal, Juan M. Pena, Thomas J. George, Jiang Bian. The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 502.
Abstract 3547: IL-12-based cytokine factories modulate tumor microenvironment to eradicate pancreatic tumors in mice and are well tolerated in non-human primates
Authors: Amanda Nash, Samira Aghlara-Fotovat, Bertha Castillo, Annie Nguyen, Andrew Cui, Andrea Hernandez, Peter Rios, Sofia Ghani, Ira Joshi, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Omid Veiseh
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is often diagnosed at advanced stages and responds poorly to chemotherapy. Because high tumor T cell infiltration corresponds with better clinical outcomes in pancreatic cancer patients, immunotherapy has gained significant interest over the last decade for the treatment of recurrent pancreatic cancer. IL-12 is a proinflammatory cytokine with pleiotropic effects including activation of CD8+ T cells and NK cells. Unfortunately, systemic high dose IL-12 administration led to severe toxicities in clinical trials which has limited further development of this cytokine as a cancer therapeutic. To address this limitation, we developed an implantable cytokine delivery platform to allow for local administration of IL-12. These cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers, allow for safe and controlled dosing in vivo. Tumor adjacent administration of IL-12-based cytokine factories caused reduction of intraperitoneal pan02 tumor burden by 80% after only 1 week of treatment in mice with pancreatic cancer. Single cell RNAseq of the tumor adjacent immune cells at this time point showed 2x more T and NK cells present in the IL-12 treated mice than untreated mice suggesting modulation of the tumor microenvironment via immune cell infiltration. Importantly, the necessary IL-12 dose was well tolerated in all mice without signs of toxicity for 180 days. In efforts to evaluate the translatability of this platform, we further tested IL-12-based cytokine factories in a non-human primate. The cytokine factories produced a high local IL-12 concentration without substantial leakage into the systemic circulation and were well tolerated by the primates as shown by the lack of fever or weight loss, as well as the lack of renal or liver toxicity. Our findings highlight the therapeutic potential of IL-12 treatments when administered locally via cytokine factories in preclinical animal models. Further, these findings provide rationale for future development and clinical testing of cytokine factories for treatment of a wide range of metastatic peritoneal cancers in humans. Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Bertha Castillo, Annie Nguyen, Andrew Cui, Andrea Hernandez, Peter Rios, Sofia Ghani, Ira Joshi, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Omid Veiseh. IL-12-based cytokine factories modulate tumor microenvironment to eradicate pancreatic tumors in mice and are well tolerated in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3547.
Abstract 6249: PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11)
Authors: Krishan K. Saini, Priyank Chaturvedi, Ayushi Verma, Mushtaq A. Nengroo, Abhipsa Sinha, Akhilesh Singh, Sanjeev Meena, Muqtada A. Khan, Manish P. Singh, Dipak Datta
Journal: Cancer Research (2022)

Abstract Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis is induced in cancer cells by inhibition of lipid peroxide quencher GPx4. System xc - imports cystine into cytosol for the biosynthesis of glutathione. Tumor cells that are resistant to chemotherapeutic drugs called ‘drug tolerant’ or ‘Persister’ cells which have distinct vulnerability towards iron mediated cell death or ferroptosis. Unfolded Protein Response (UPR) plays critical role for cancer cells to become drug tolerant. Tweaking the balance of UPR to make drug tolerant cells susceptible to Ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in ferroptosis, we investigated the status of UPR following treatment of potent ferroptosis inducer RSL3 (Ras Selective Lethal) in colon cancer cells. We observed an overall up-regulation of UPR activators (ATF6, IRE1α and PERK) and their downstream effectors along with a marked overexpression of cystine-glutamate transporter (System xc -). To further delineate the contribution of particular UPR arm in modulating System xc - expression and subsequent ferroptosis, we made stable knock down cells of each UPR arm and discovered that PERK is selective and critical in inducing ferroptosis in colon cancer cells. Loss of PERK function not only promotes ferroptosis via increasing lipid peroxidation but also limits in vivo tumor growth in colon xenograft model. Further, we find that low PERK expression is associated with higher patient survival as per TCGA COLON CANCER (COAD) database. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and genetic silencing of PERK sensitizes colon cancer cells to selective Ferroptotic cell death. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics that can sensitize apoptosis resistant cancer cells towards Ferroptotic cell death. Citation Format: Krishan K. Saini, Priyank Chaturvedi, Ayushi Verma, Mushtaq A. Nengroo, Abhipsa Sinha, Akhilesh Singh, Sanjeev Meena, Muqtada A. Khan, Manish P. Singh, Dipak Datta. PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6249.
Abstract 3900: Β3 adrenergic receptor blockade impairs compensatory mechanism to overcome nutrient deprivation in malignant rhabdoid tumor of the kidney
Authors: Angela Subbiani, Alessia Boaretto, Daniela Buonvicino, Cecilia Cecchi, Claudio Favre, Maura Calvani
Journal: Cancer Research (2022)

Abstract In this study, the effects of nutrient deprivation in regulating tumor growth and metabolism in Malignant Rhabdoid Tumor of the Kidney (MRTK) was investigated. MRTK is a rare and highly aggressive tumor occurring in infancy and early childhood. Unfortunately, there are not many studies to date that can help us better understand the involvement of metabolism in MRTK growth and progression. However, it is now well known that nutrient deprivation is an environmental stress factor that can influence the behavior of cancer cells leading to reprogramming in metabolism. Here, we first evaluated the effects on cell survival and metabolic adaptation of MRTK G-401 cells after glutamine or tyrosine/phenylalanine deprivation, or both. Then, the involvement of the β3-adrenergic receptor (β3-AR) in regulating the metabolic changes in G-401 cells exposed to limited conditions was investigated. We demonstrated that deprivation of glutamine alone or in combination with tyrosine/phenylalanine enhanced the expression of the glucose transporter GLUT1, associated with increased glucose uptake, ATP production, and oxidative stress, as a compensatory mechanism following amino acid deprivation partially regulated via β3-AR. Indeed, β3-AR antagonism was able to decrease the expression of GLUT1, glucose uptake and survival in G-401 cells. Furthermore, exposure of G-401 cells to limited conditions induced an improved activity of the TCA cycle enzymes leading to a different and enhanced fumarate production. Overall, our results indicate that tyrosine/phenylalanine and glutamine deprivation in MRTK is able to trigger a compensatory mechanism to sustain tumor growth and proliferation. Citation Format: Angela Subbiani, Alessia Boaretto, Daniela Buonvicino, Cecilia Cecchi, Claudio Favre, Maura Calvani. Β3 adrenergic receptor blockade impairs compensatory mechanism to overcome nutrient deprivation in malignant rhabdoid tumor of the kidney [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3900.